Cyclopentanophenanthrene derivatives and process



Patented Nov. 20, 1951 -UNITED STATES PATENT OFFICE H q 2,375,840 CYCLO'PENTANOPHENANTHBENE DERIVA- TIVES AND PROCESS George Rosenkranz and Stephen Kaufmann,

Mexico City, Mexico, assignors to Syntex, S. A., Mexico City, Mexico, a corporation of Mexico No Drawing. Application March 2;, 1948, Serial No. 16,884. In Mexico September 20, 1947 7 Claims. (01. 260-23955) 1 o 2 p The present invention relates to novel cyclobe converted to compoundsrepresentd by the pentanophenanthrene derivatives and a process following two tautomeric formulas: 1 for producing the same. More particularly the 0113 CH; CH; f 1 a a present invention relates to novel derivatives of cyclopentanophenanthrene substituted by a side 5 H 0 CH2 GHTAFH x chain at the 17 position and by a keto group at 0H the 16 position.

In its more specific aspects, the present invention is directed to the production of novel compounds, namely 16 dihydrokryptogenin and the esters thereof, to a process for producing the same, and to the production of steroidal sapog- I y enin derivatives from 16 .dih'ydrokryptogenin 91 and/ or its esters, these derivatives being especially suitable as intermediates in the manufacture of hormones.

The steroidal sapogenin kryptogenin was first described by Marker, Wagner, Goldsmith, Ul-

shaier, and Ruof (Journal of American Chemical St g d diff e tl it ha been w efdjhfif.

Society, 65739 (1943)), and the following 20 nickel catalyst, o xa p un r ub' fin.

formula was Suggested: tially neutral conditions is selective in its action 0H; CH1 CH3 0 and hydrogenation takes place at the 16 position. E The above reaction is especially applicable to Y I 5 hydrogenation 1n the 16 position of kryptogenin 0 l and its esters in accordance with the following equation: a a

CH3 CH3 CH3 0 It was also suggested in the same article that a 0 Hi kryptogenin could be converted in etherial solu- Nmyst tion into 5,6-dihydrokryptogenin by catalytic s fif hydrogenation in the, presence ofsmall amounts Z ,1k,1,f;%,edum of acetic acids and Adams catalyst. n Kryptogenln or its esters The surprising discovery has been made iii CH3 CH3 CH3 0 accordance with the present invention, however, H GH Cfi CH -CH z that, by utilizing a finely divided nickel catalyst, 5 asi'or example, Raney nickel, and in a slightly L 6 i alkaline or neutral medium, derivatives of cyclopentanophenanthrene having a. keto group at the 16 position and a side chain at the 1? position,

can be hydrogenated at the 16 position whether or not there is present an unsaturated group else- 16 dillydrlkrypmgemn 0r ester y where in the phenathrene nucleus. As, for ex- In the abov? formula, Z may 9 7 ample, compounds according to the following acyl am r substantlany general formula: phatic saturated radical or an aromatic satum CH3 CH8 0 rated radical. For example, if the acyl group is g g p an aliphatic saturated radical it maybe the U: residue of any suitable fatty acid and preferably 0 v alternative, the residue of an aromatic saturated acid may be utilized as, for example, benzoic.

The cyclopentaneophenanthrene nucleus may also contain substitunts providing these substi- A l a, tuent groups do not interfere with the hydrogenawhereiii Xis a CHQOI-ll group or a group" ccnvertion. For example,- 5,6 dihydrokryptogenin pretoa CHz'OI-I group, as, for' xamplej ,CCi'OR, pared in accordance with the processes of the CQOH, or CHOR), Y is an'OH group or an prior art may be further hydrogenated in ac- OR group and R is anyi saturate'd aliphatic or cordance with the present. invention, to 5,6-16

aromatic radical incapable ofeasy reduetitdcafl t'etrahydrokryptogenin. The esters of l fi-dihy- CH3 the lower fatty acids, such as acetic. In

3 '1; L" 5 drokrypto'genin may be converted "w lfi-rdihydro-v kryptogenin by hydrolysis in an alkaline medium and lfi-dihydrokryptogenin may be converted to the esters of lfi-dihydrokryptcgenin.hyitre atment with acylating agents at room temperatures preferably in the presence of tertiary amines such as pyridine or dimethyl aniline. The'se reactions are illustrated by the following'equa-i r1;-

tions:

5 I 7 1 0111'". .5 CHr-CHz-iH-QHQQAQ Alkaline hydrolysis R Acylating agents at room temperature in presence of tertiary amines lfi-dihydrokryptogenin esters en. 7 e

Thetreatment of lfi-dihydrokryptogenin with an acylating agent, for example acetic anhydride, and with heating produces the acyl derivatives of diosgenin in accordance with the following equation: 4

CH; OH:

OH CH2! I CHPCHPCHfGHZOH heat, acylatingagent v We i Acyl O Q ii-he treatment of the esters I dihydrokryptogenins with dehydrating agents as, for example, tetrahydronaphthalene, phosphorus oxyitmofidaaaayi chloride, etc. the last two preferahly-in; the presence of tertiary amines as, for

example etr'mnie'ei dimethyl aniline, produces CH: CH;

cnf-tH-cmon V lfi-diliydrokryptogenin esters of pseudo-diosgenin in accordance with: the-following equation:

OH G

dehydrating crept.

CH3 cHrcm-tn-cmo Acyl I Pseudcdlosgenin diacylate ln every case the foregoing reactions" are;

7 generally applicable to the 5,6 dihydrokryptof genin and its lfi-dihydrokryptogenin' derivativesf namely the 5,6-16 tetrahydrokryptogenin or derivatives thereof For example when 5,65 tetrahydrokryptogenin is treated with a'rel tively strong acid, tigogenin is producedflhe following specific examples serve to illustrate the present invention but are not intended tog" limit' the same.

Example I v 60 grams of kryptogenin were dissolved cc. of alcohol and 30 grams of Raney nickel were; added. The mixture was thenagitat'ed in a hydrogen atmosphere for approximately two hours. The nickel was then filtered off and the alcoholic solution evaporated to dryness. The residue was recrystallized from acetone to give lfi-dihydrokryptogenin having a melting 'point of V 173-175 C.

Example II 10 grams of the lfi-dihydrokryptogenin. .01. Example I were dissolved in 50' cc. of cold glacial acetic acid. After standing for five minutes...pi ire diosgenin, having a melting point of 202-20 f 0.. crystallized therefrom.

Example III grams of the lfi-dihydrokrypto genin of Example I were dissolved in 30 cc. of acetic anhydride and refluxed for a half-hour. The solution was then cooled and after cooling 9. product crystallized which was identified as diosgenin acetate. The product was recrystallized from ethyl acetate and was found to have a melting point of 1965-498" C.

Example I V 60 grams of kryptogenin diacetate were dissolved in 1200 cc. of alcohol and 30 grains of Barley nickel were added. The mixture was agitated in a hydrogen atmosphere for two hours. The nickel was filtered oil and the alcoholic som tion evaporated to dryness. The residue was a colorless viscous oil which did not crystallize. Further reactions with the residue indicated that it was the diacetate of lfi-dihydrokryptogenin.

Example V 30 grams of the is-dihydrokryptogenin diacetate of Example IV were dissolved ih300 cc. of alcohol containing 30 grams of potassium hydroxide. The reaction mixture was refluxed for half an hour. At the end of this time the mixture was poured into water and extracted with ether. The ether solution was washed free from alkali with water and the neutral solution was dried and evaporated to dryness. The residue was crystallized from acetone to give ifi-dlhydrokryptogenin. Melting point 1731'75 C.

Example VI 10 grams of the lfi-dihydrokryptogenin diacetate of Example IV were dissolved in 100 cc. of alcohol containing 10% of hydrochloric acid. The mixture was refluxed for five hours. At the end of this time the mixture was poured into water and the crystalline precipitate filtered on. Upon recrystallization from alcohol, pure diosgenin was obtained having a melting point of 202-203 C.

Example VIII 10 grams of the lfi-dihydrokryptogenin of Example I were dissolved in 200 cc. of pyridine and 20 cc. of acetic anhydride at room temperature. After standing 24 hours, the reaction mixture was poured into water and extracted with 0 CHa-L ether. The ether solution was washed withwater until neutral, dried and evaporated to dryness. The residue was a viscous oil which did not crystallize: and proved. to be the diacetate of lfi-dihydrokryptogenin. similar to Example IV.

It will be obvious to those skilled in the art that various changes may be made without departing from the spirit of the invention. and therefore the invention is not limited to what is described in the specification but only as indicated in the appended claims.

What is claimed is:

I. As a new product the -16-dihydro cyclopentanophenanthrenes selected from the group consisting of compounds having a. general formula selected from the group consisting of:

ll CH:

wherein Z in each instance is selected from the group consisting of OH and O-acyl and acyl is selected from the group consisting of a fatty acid radical and a benzoic acid radical and the corresponding 5,6-dihydro compounds.

2. As a new product lfi-dihydrokryptogenin having a melting point between FIB- C. and the general formula selected from the group consisting of:

3. As a new product the diacetate of 16-dihydrokryptogenin having a general formula selected from the group consisting of:

CHI CHI CHI 0 arcasm and the tautomer, w 1

CH1 1 CH: 0H CH3 Clara-O ence of a finely divided nickel'catalyst to pro-.-

duce the corresponding 16-dihydro derivatives.

5. A process for the productionof lfi-dihydrokryptogenin comprising hydrogenating kryptogenin in a-substantially neutral medium and in the presence of a nicke1 catalyst.

6. A process for the production of 5,6-16- tetrahydrokryptogenin comprising hydrogenating 5,6-dihydrokryptogenin in a substantially CHz-C'HrCH-CHrneutral medium and in the presence of a nickel catalyst.

7 A process for the production of lfi-dihydrokryptogenin diacetate which comprises hydrogenating in a substantially neutral medium kryptogenin diacetate in the presence of a nickel cataly'st to produce lfi-dihydrokryptogenin diacetate.

' GEORGEROSENKRANZ.

STEPHEN KAUFMANN'.

REFERENCES CITED The following references are of record in the fileof-this patent:- V

"UNITED STATES PATENTS 7 V 4 7 Date Number Name 2,352,850 Marker, July 4, 1944 2,408,832 Wagner Oct. 8, 1946 OTHER REFERENCES Marker et al., J; Am. Chem. Soc., vol. 65. p. 739 (1943).

Marker et in, J. Am. Chem soc, v61; 65, pp. 

1. AS A NEW PRODUCT THE 16-DIHYDRO CYCLOPENTANOPHENANTHRENES SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS HAVING A GENERAL FORMULA SELECTED FROM THE GROUP CONSISTING OF: 